The classical transplantation antigens (the major histocompatibility complex class I antigens) play a key role in host defense against cells expressing foreign antigens. Several naturally occurring tumors and virally transformed cells show an overall suppression of these surface antigens. Since the class I molecule are required in the presentation of neoantigens on tumor cells to the cytotoxic T-lymphocytes, their absence from the cell surface may lead to the escape of these tumors from immunosurveillance. To test this possibility, a functional class I gene was transfected into human adenovirus 12-transformed mouse cells which do not express detectable levels of class I antigens; the transformants were tested for expression of the transfected gene and for changes in tumorigenicity. The expression of a single class I gene, introduced by DNA-mediated gene transfer into highly tumorigenic adenovirus 12-transformed cells, was sufficient to abrogate the tumorigenicity of these cells. Treatment of adenovirus 12-transformed cells with interferon led to derepression of the endogenous class I genes. Rejection of human adenovirus (Ad12) tumors was observed with intramuscular injections of interferon. Interestingly, Ad12 tumor cells treated with interferon can immunize mice against untreated Ad12 tumors.